Methylvinyl ketone (MVK), ethylvinyl ketone (EVK), and 2- cyclohexen-1-one (CHX) were nominated and selected for study by the NTP as part of a class study on alpha,beta-unsaturated ketones. MVK is a representative noncyclic member of the major class of straight-chain aliphatic alpha,beta-unsaturated ketones. EVK is a secondary conjugated carbonyl compound from the subclass of aliphatic alpha,beta-unsaturated ketones. CHX is a prototype of the cyclic alpha,beta-unsaturated ketones. Prechronic Inhalation studies of these ketones were conducted to characterize and compare the relative toxicities and also to facilitate the design of chronic inhalation studies of these chemicals. This chemical class study will allow more accurate prediction of the potential toxicity and carcinogenicity of other untested alpha,beta-unsaturated ketones. Prechronic studies (14- and 90-day) of CHX, MVK and EVK were conducted in B6C3F1 mice and F344 rats. The same study design was used for all three chemicals. In the 90-day studies, rats and mice were exposed to 2.5, 5, and 10 ppm CHX; 0.5, 1, and 2 ppm MVK, and 2, 4, and 8 ppm EVK. Blood and tissue samples were collected and analyzed for changes in clinical pathology, SMVCE, micronucleus assay, and histopathology. All three ketones were direct-acting irritants and targeted the upper respiratory tract at low exposure concentrations and the upper and lower respiratory tract at higher exposure concentrations. Nasal lesions included olfactory epithelial regeneration, and metaplasia (respiratory), as well as respiratory epithelial hyperplasia and metaplasia (squamous). In general MVK was the most reactive, causing nasal lesions at lower concentrations than either EVK or CHX. EVK was slightly more potent than CHX based upon a greater incidence of respiratory epithelial hyperplasia and chronic inflammation in the lung. These lesions occurred at a lower incidence or were absent in animals exposed to similar concentrations of CHX. Upper respiratory tract lesions were similar for all three ketones and were typical of lesions caused by inhaled direct-acting irritants.